Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides
  • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
  • A61K38/06—Tripeptides
  • A61K38/066—TRH, thyroliberin, thyrotropin releasing hormone
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/04—Anorexiants; Antiobesity agents

Definitions

• the invention relates to the preparation of food supplements for man or animal essentially based on thyrotropin-releasing hormone (TRH), a tripeptide, i.e. (pyro)Glu-His-Pro NH2 or salts thereof suitable for food consumption (hereafter designated as "dietary salts"), such as a TRH tartrate.
• TRH thyrotropin-releasing hormone
• dietary salts such as a TRH tartrate.
• TRH is known to of provide for the restoration of thymic and thyroid functions which normally undergo decay in the course of aging, for the reduction in body fluids, particularly blood serum, of elderly people, of the contents of lipid-related compounds, e.g. cholesterols, triglycerides and phospholipids, associated with arteriosclerosis or related diseases, particularly arterial and venous thromboses. It has been shown, particularly in international application PCT/EP 90/00209, that TRH treatment of aging mice (18 month-old mice) causes the levels of cholesterol, triglycerids and phospholipids to be brought back to values currently observed in young mice, e.g. three month-old mice.
• lipid-related compounds e.g. cholesterols, triglycerides and phospholipids
• compositions preferably food additives, or even foods supplemented with such food additives (it being understood that the expression "food” as used herein is intended to encompass beverages), whose active component consists of TRH or dietary (or pharmaceutically) acceptable salts thereof.
• food as used herein is intended to encompass beverages
• active component consists of TRH or dietary (or pharmaceutically) acceptable salts thereof.
• these compositions are active in preventing fat depots of being formed as a result of food intake or even causing fat depots that have already accumulated to be reduced.
• TRH has no substantial appetite satiation effect.
• Any dietary salt suitable for intake y man or animal can be used.
• Watersoluble salts are preferred. Tartrates have already mentionned as consisting of particularly valuable salts for fulfilling such purposes. Examples of other suitable salts are acetates, citrates, etc. Needless to say that when reference is made herein to TRH, it must be understood that these salts are also encompassed by that abbreviation, except when and if stated otherwise.
• TRH When used as a food additive or supplement, TRH will of course be absorbed orally before, after, simultaneously with food intake or between meals. Intake of TRH can occur either in solid form or, particularly when in the form of a sufficiently soluble salt, with drinking water or other beverages. Advantageous daily doses may range between 1 and 20 mg, it being understood that such figures are in no way limitative of the amounts that can be taken. TRH is an absolutely safe molecule and far greater amounts thereof can be absorbed without any risk.
• TRH may indeed be associated with other compounds active as " oxidative burners" of fat depots. It is preferred that the associated compounds not exert a satiety effect of their own, e.g. like cholecystokinin or an active peptide fragment thereof, such as the C-terminal octapeptide known under the abbreviation CCK-8 or under the now classical designation "sincalide”.
• preferred compositions aim at normalizing body weight, particularly in obese people or people having a tendency towards obesity (or obese animals or animals having a tendency towards obesity), more generally of upkeeping fat deposits or fats that normally form as a result of food intake under control even in persons with normal endocrine functions, yet without interfering with normal appetite of those who absorb them.
• compositions of the invention are free of appetite-cutter or satiation-causing components. They may of course include other components capable of stimulating the endogenous production of TRH in the host, e.g. melatonin.
• TRH or its salts are preferably used as food dietary supplements, they are also suitable for use in the manufacture of drug compositions for control of adiposity, including the cure of obesity.
• the above dosages are indicative of the daily doses that can be used for therapeutical purposes by the oral route.
• TRH may be administered in the form of capsules containing 5mg each.
• these drug compositions are preferably in a form (solid or liquid) suitable for administration by the oral route, it goes without saying that other administration routes, e.g. any parenteral route, can be contemplated.
• TRH can be associated with other components which are likely to also stimulate the endogeneous production of TRH in the host, e.g. melatonin.
• TRH compositions of the invention are in a form which will provide for a protection of the active principle against the gastric acidity.
• TRH is either the base or the salt, e.g. the tartrate.
• Preferred embodiments of the invention comprise TRH- containing capsules coated with acid-(stomach)-resistant pellicles, of any nature e.g. cellulose films suitable for providing a more uniform release in the guts rather than in the stomach.
• TRH thyrotropin releasing hormone
• mice C57BL/6 male mice aged 7 months (AHA-lesioned at 2 months of age to induce obesity), were injected intraperitoneally for 20 days at 6 pm (evening) with 0.5 ml volume containing 10 ⁇ g TRH-tartrate in bidistilled water. Controls were injected with the same amount of diluent. 48-day treatment with thyrotropin releasing hormone (TRH) normalizes the body weight of anterior hypothalamic area (AHA)-lesioned obese mice.
• TRH thyrotropin releasing hormone
• mice C57BL/6 female mice aged 8 months (AHA-lesioned at 2 months of age to induce obesity), were injected intraperitoneally for 48 days at 6 pm (evening) with 0.5 ml volume containing 10 ⁇ g TRH-tartrate in bidistilled water. Controls were injected with the same amount of diluent.
• TRH cannot increase, beyond a certain level, synthesis and release of thyroid hormones even at those very high dosages of parenteral administration:
• mice C57BL/6 male mice aged 9 months, were injected intraperitonealy for 20 days at 6 p.m. (evening) or at 8 a.m. (morning) with 0.5 ml volumes containing either 10 ⁇ g or 100 ⁇ g of TRH in bidistilled water. Controls were injected with the same amount of diluent. The mice were bled from the retroorbital venus plexus under rapid acute ether anaesthesia at 10 a.m. T3, T4 and TSH were measured by radioimmunoassay in the serum of individual mice. Effect of 20 days treatment with thyrotropin releasing hormone (TRH) on blood levels of T3, T4 and TSH in mice. Groups (G) Treatment No.
• TRH thyrotropin releasing hormone
• the very basic Table 8 shows that oral, chronic administration of TRH in the drinking water of aging mice is effective in preventing the typical increase of body weight and adiposity which accompanies the initial stage of aging, which is also visible in humans everywhere!
• progressive alteration of pineal-hypothalamic-pituitary-peripheral endocrine glands function in the course of aging leads to the most typical appearance of decreased tolerance to glucose (hyperglycemia), increased levels of lipids, in particular triglycerides and cholesterol (hyperlipidemia) and progressive accumulation of fat, which is not obesity but the most common expression of hormonal derangements.
• TRH taken chronically will maintain normal body weight in normal aging mice, while the normal controls put on fat and weight.
• TRH is also capable of preventing onset of aging-related adiposity in humans.
• TRH given chronically by oral route prevents the increase of aging-related adiposity in old female mice.
• Treatment with TRH-tartrate in the drinking water 100 ⁇ g/ml was started in 16 month-old BALB/cJ X C57BL/6 F1 female mice, and continued for 5 months.
• the activities of melatonin and TRH can potentiate each other considerably when they are administered simultaneously or sequentially, it being nevertheless understood that in the latter instance the time interval which would separate the two administrations should nevertheless be small enough to provide for the simultaneous presence of melatonin and TRH in the blood circulation of the host.
• the invention relates to pharmaceutical compositions containing both thyrotropin-releasing hormone and melatonin in relative amounts providing for a synergistic effect of their respective anti-obesity activities.
• compositions of the invention comprise both TRH and melatonin. They provide for enhanced metabolizing effect of fat depots.
• the invention relates more particularly to compositions for systemic administration to man or animal (or to the preparation of such compositions, particularly for the treatment of obesity of both melatonin and TRH in relative synergistically effective amounts, in association with a suitably physiologically acceptable carrier chosen depending upon the required route of administration.
• the invention relates also more particularly to compositions containing both melatonin and TRH associated with ointments, lotions or any other vehicles allowing for topical applications of said compositions.
• Preferred conditions of use of TRH and melatonin, as associated with each other, with a view of achieving the above-mentioned results comprise administering to the living host the relative effective doses of said TRH and melatonin in one of the administration forms which have been mentioned above, preferably from sunset, or a little earlier, say from 4 P.M., up to the time where the host goes to sleep.
• Examples of said daily doses capable of inducing a favorable effect range from 0.1 to 1 mg of TRH and of from 0.01 to 1 mg of melatonin per kg of body weight, when the administration is effected by the oral or rectal route, or 0.005 to 0.1 mg of TRH and of from 0.01 to 1 mg of melatonin, per kg of body weight, when administered by the parenteral route.
• topical compositions may contain from 0.005 to 5% in weight of melatonin and from 0.001 to 5% in weight of TRH.
• TRH and melatonin may also be administered by other routes, e.g., by the rectal route.

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• Health & Medical Sciences (AREA)
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• Animal Behavior & Ethology (AREA)
• General Health & Medical Sciences (AREA)
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• Diabetes (AREA)
• Child & Adolescent Psychology (AREA)
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• General Chemical & Material Sciences (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Endocrinology (AREA)
• Organic Chemistry (AREA)
• Obesity (AREA)
• Proteomics, Peptides & Aminoacids (AREA)
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• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Coloring Foods And Improving Nutritive Qualities (AREA)
• Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
• Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
• Medicines Containing Plant Substances (AREA)

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Cited By (2)

Citations (3)

• 1999
  • 1999-11-03 EP EP99402733A patent/EP1097716A1/fr not_active Withdrawn
• 2000
  • 2000-11-02 WO PCT/EP2000/010791 patent/WO2001032195A1/fr active Search and Examination

Patent Citations (3)

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